Heart failure is a pathophysiological condition in which the heart fails to pump blood at a rate commensurate with the requirements of the metabolizing tissues of the body. Heart failure is a principal complication of virtually all forms of heart disease.
In the failing human heart, numerous changes occur in receptor signal transduction pathways. In particular, there is impairment of the myocardial .beta.-adrenergic receptor (.beta.AR) system.
Receptors coupled to heterotrimeric guanine nucleotide-binding proteins (G proteins), such as the adrenergic receptors, increase cellular concentrations of second messengers, such as cyclic adenosine 3', 5'-monophosphate (cAMP), thereby regulating cellular function. The binding of the catecholamines norepinephrine and epinephrine to .beta.ARs in the heart stimulates adenylyl cyclase, raises the concentration of cAMP, and increases cardiac contractility. Increased secretion of catecholamines and stimulation of myocardial .beta.ARs are critical for augmenting cardiac function during exercise and stress.
One of the best documented changes that occurs in heart failure is the differential down-regulation of the .beta..sub.1 -adrenergic receptor (.beta..sub.1 AR). This is accompanied by an uncoupling of the .beta..sub.2 -adrenergic receptor (.beta..sub.2 AR) and, perhaps, also the .beta..sub.1 AR, from adenylyl cyclase stimulation so that the failing heart is less able to respond to .beta.AR agonists and to the demands of stress and exercise. In addition, the .beta..sub.1 AR signal transduction pathway is presumed to be responsible for producing adverse biological effects in cardiac myocytes associated with chronic activation of the adrenergic nervous system. Therefore, chronic overstimulation of this receptor pathway may contribute significantly to the downward progression of heart failure.
Bertin et al. have described a transgenic mouse overexpressing human .beta..sub.1 AR. Bertin et al., Cardiovasc. Res., 27, 1606-1612 (1993); PCT application WO 94/04668. Receptor overexpression was targeted exclusively to the atria by using the human a trial natriuretic factor promoter. Statistically significant phenotypic effects were not generated, although an excess of premature supraventricular beats was observed in 43% of the transgenic mice.
Milano et al. have described the creation of a transgenic mouse overexpressing the human .beta..sub.2 AR using a murine .alpha.-myosin heavy chain (.alpha.MHC) promoter. Milano et al., Science, 264, 582-586 (1994); Milano et al., J. Thoracic Cardiovasc. Surg., 109, 236-241 (1995). The use of this promoter targeted gene expression to the myocardium, both in the atria and ventricles. Myocardial and ventricular function were reported to be enhanced. No pathologic changes were observed in mice up to four months of age. In particular, no heart failure or cardiomyopathic phenotype was reported.
Milano et al. suggest the potential of their approach for the treatment of heart failure by gene therapy. However, they teach against using genes coding for .beta..sub.1 ARs (see page 583, second column of Milano et al., Science, 264, 582-586 (1994)).